tbuckley/cabot-search huggingface dataset:
Abstract 310: Harness small peptide to improve anti-cancer effect of PD-1 checkpoint inhibitor in melanoma-bearing obese mice
Authors: Seungmin Han, Kelsey E. Decker, Young-Wook Won
Journal: Cancer Research (2022)

Abstract Obesity-associated chronic inflammation and adipokine increase the cancer risk through promotion of tumor growth and malfunction of immune cells. Leptin, an adipokine abundantly found in obesity, is positively correlated with PD-1 expression and up-regulation of PD-1 on immune cells leads to immune cell exhaustion. PD-1 blockade (checkpoint inhibitor) has shown promising anti-tumor efficacy in patients with obesity through direct effects on the up-regulated PD-1. However, there are still need for improving the response rate and the efficacy of PD-1 blockage. In our previous study, we have verified that prohibitin binding peptide (PBP) inhibits glucose metabolism of cancer cells, resulting in alterations in pro-tumor tumor microenvironment (TME) to pro-immune TME. The pro-immune TME reinvigorates anti-cancer activity of immune cells and results in better suppression of tumor growth. Based these findings, we hypothesized that PBP would improve the anti-cancer effect of PD-1 checkpoint inhibitor on cancer with obesity. Melanoma was embedded in lean or obese mice, then the mice were assigned to one of following groups: i) PBS, ii) PBP, iii) anti-PD-1 antibody (aPD-1) and iv) combination of PBP and aPD-1 (PBP+aPD-1). The PBP+aPD-1 group showed improved anti-cancer efficacy in tumor-bearing obese mice (not in lean mice) compared to single aPD-1 injection. Immune cells in PBP+aPD-1 injected obese mice showed the more activated characteristics in terms of its cytokine secretion and phenotype. In addition, the serum leptin level was decreased upon PBP treatment, indicating that the PBP-mediated decrease in the serum leptin level attributed the rejuvenation of immune cells through the balanced PD-1 expression on immune cells. PBP improves the anti-cancer efficacy of aPD-1 on tumor with obesity through recovering anti-cancer activity of immune cells that is driven, at least in part, by a decrease in the glucose metabolism of cancer cells and the circulating leptin levels. Consequently, combination of PBP and aPD-1 would have the great potential to treat cancer patients with obesity. Citation Format: Seungmin Han, Kelsey E. Decker, Young-Wook Won. Harness small peptide to improve anti-cancer effect of PD-1 checkpoint inhibitor in melanoma-bearing obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 310.
Abstract 557: Engineering off-the-shelf anti mesothelin t-cell receptor fusion construct (TRuC™) t-cells
Authors: Julie Donaghey, Cecilia Kwong, Allison Powell, Troy Patterson, Ella Liberzon, Richard Decker, Julio Gomez Rodriguez, Darby Kreienberg, Jennifer Bian, Urmi Patankar, Holly Horton, Jian Ding, Robert Hofmeister, Dario Gutierrez, Robert Tighe
Journal: Cancer Research (2022)

Abstract We have previously described the generation of autologous T Cell Receptor Fusion Construct (TRuC™) T cells which are engineered to express a fusion protein comprised of an antibody-derived binder tethered to the extracellular domain of the CD3ε signaling subunit. Upon integration of the TRuC into the T cell receptor (TCR), it targets specific tumor surface antigens independent of HLA and uses the complete receptor complex to trigger a comprehensive T cell response. Here, we report about engineering of off-the-shelf TRuC-T cells directed against mesothelin (MSLN). To eliminate the alloreactivity of α/β T cells and reduce the risk of graft-versus-host-disease (GvHD), the TRAC locus is knocked-out. To enable the re-assembly of the TCR, the endogenous TCRα and β subunits are replaced with fusion proteins comprised of antibody-derived binders fused to the TCRγ and δ constant domains. Allogeneic anti-MSLN TRuC-T cells upregulate activation markers, secrete robust cytokines, and lyse tumor cells in an antigen-specific manner without allo-reactivity. In comparison with control autologous TRuC-T cells targeting mesothelin (TC-210), allogeneic TRuC-Ts demonstrate extended tumor clearance in NSG xenograft models due to their enhanced expansion and persistence. To reduce host rejection and further boost the persistence of the allogeneic TRuC-T cells, we eliminated MHC class I surface expression by B2M gene knockout and over-expressed membrane-bound IL15 tethered to its receptor alpha. In summary we have engineered persistence enhanced, allogeneic TRuC-T cells that maintain the signaling properties of the TCR complex with improved efficacy compared to donor-matched autologous TRuC-T cells. Citation Format: Julie Donaghey, Cecilia Kwong, Allison Powell, Troy Patterson, Ella Liberzon, Richard Decker, Julio Gomez Rodriguez, Darby Kreienberg, Jennifer Bian, Urmi Patankar, Holly Horton, Jian Ding, Robert Hofmeister, Dario Gutierrez, Robert Tighe. Engineering off-the-shelf anti mesothelin t-cell receptor fusion construct (TRuC™) t-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 557.
Abstract 5844: A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients
Authors: xiangyu sun, Zhichao Fu
Journal: Cancer Research (2022)

Abstract Background: Many patients with cancer have benefited from immunotherapy represented by the blockade of immune checkpoint PD-1/PD-L1. However, about 4-29% of cancer patients treated with immunotherapy developed hyper-progressive diseases(HPD) with accelerated tumor growth. MDM2/MDM4 amplification was suggested as genomic correlates for elevated risk hyperprogression. The objective of this study was to evaluate the frequency of amplification of MDM2/MDM4 in the Chinese solid tumor patients and to provide advice on the selecting of optimal treatment decisions. Methods: Tumor or blood samples were collected from 2,937 patients with solid cancer, genetic mutations and amplification was detected using the next-generation sequencing(NGS). Results: A total 112 patients with MDM2/MDM4 amplification were identified, including lung cancer 50.9% (57/112), colorectal cancer 14.3% (16/112), gastric cancer 8.0% (9/112), liver cancer 5.4% (6/112), Biliary tract cancers 4.5% (5/112), breast cancer 2.7% (3/112), and pancreatic ductal adenocarcinoma 2.7% (3/112). TMB value was identified, The median TMB for lung cancer was 9.13 mutations/Mb, median TMB for colorectal cancer was 13.8 mutations/Mb, a high TMB value in gastric cancer (median TMB=20.22 mutations/Mb), and median TMB for liver cancer was 17.9 mutations/Mb. Meanwhile, MSI was detected in 8% of patients with MDM2/MDM4 amplification, of which 3 in lung cancer, 5 in colorectal cancer, and 1in gastric cancer. Conclusions: Although amplification of MDM2/MDM4 was observed only in a small proportion of patients, it demonstrated an association with high TMB in several common cancer types. In addition, our data indicate that amplification of MDM2/MDM4 in different types of cancer is heterogeneous and that an appropriate immunotherapy strategy for patients with solid cancer should be noted. Citation Format: xiangyu sun, Zhichao Fu. A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5844.
Abstract 5549: First-in-class TNFR2 agonist &amp; antagonist antibodies as Treg-Teff modulator for cancer immunotherapy
Authors: Xiaoling Jiang, Chonging Wu, Liusong Yin
Journal: Cancer Research (2022)

Abstract Tumor necrosis factor receptor 2 (TNFR2) is expressed on highly suppressive tumor-infiltrating T regulatory cells (Treg), activated T effector cells (Teff), as well as many tumor cells in the tumor microenvironment, which makes TNFR2 a novel and very promising target for cancer immunotherapy. We have identified and characterized a wide panel of first-in-class highly selective TNFR2 agonist and antagonist antibodies, from murine hybridoma and camelid phage display campaigns. Our Treg antagonist lead candidate IAT0981-1A8 is a humanized single domain antibody (VHH), which showed tight TNFR2 binding with low-digit nanomolar affinity. IAT0981-1A8 potently blocked ligand TNFa binding to TNFR2, and elicited strong Treg proliferation inhibition activities. Our Teff agonist lead candidate IAT0981-231 is a humanized monoclonal antibody with sub-nanomolar affinity to TNFR2, which potently stimulated CD8+ T cell activation, proliferation and cytokine secretion, without blocking endogenous TNFa activity. Both IAT0981-1A8 and IAT0981-231 did not cross-react with TNFR1, and exhibited extremely potent tumor growth inhibition activities as single agent in multiple tumor models in TNFR2 transgenic animals, better than tested benchmarks. Our epitope binning studies demonstrated that IAT0981-1A8 and IAT0981-231 bound to totally different epitopes on TNFR2. We also evaluated several bispecific antibodies composing of tumor associated antigens or other immune cell modulators in tumor microenvironment, with either IAT0981-1A8 or IAT0981-231. We have generated high quality commercial stable cell line for the Teff agonist lead candidate IAT0981-231, and completed several batches of 200L non-GMP and GMP production. Our preclinical cynomolgus monkey toxicity studies revealed extremely good safety profile for IAT0981-231, with no significant toxicity observed even with high 200mg/kg repeated dose. We are currently performing IND-enabling studies for the agonist lead candidate IAT0981-231, and aim to enter clinical studies in the first half of 2022, with first-in-class potential as monotherapy and I/O combination therapy for advanced cancers. Citation Format: Xiaoling Jiang, Chonging Wu, Liusong Yin. First-in-class TNFR2 agonist &amp; antagonist antibodies as Treg-Teff modulator for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5549.
Abstract 946: Utility of intestinal organoids to model serrated colon cancer <i>in vitro</i>
Authors: Prem K. Premsrirut, Huaien Wang, Eduardo J. Garcia Reino, Isabella Breen, Ana A. Vasileva
Journal: Cancer Research (2022)

Abstract Serrated colorectal cancer (CRC) is an aggressive and treatment-resistant form of colorectal carcinogenesis that accounts for one-fourth of the patients with CRC1. At the molecular level, serrated CRC is characterized by epigenetic modifications termed the CpG Island Methylator Phenotype (CIMP) and the presence of somatic mutations that activate the mitogen-activated protein kinase (MAPK) pathway1,2,3. The BRAFV600E is an early genetic change in serrated polyps, but it is not sufficient to drive tumor formation. Combinations of mutations and epigenetic modifications in P16INK4A, MLH1, ZNFR3, RNF43, and TGFBR2 are often seen in most patients4. Therefore, a combinatorial approach to develop BrafV600E-driven serrated CRC organoids harboring a variety of the above mutants will enable in vitro studies of the tumorigenic potential of each combination as well as allow engraftment into animals. In turn, the latter will allow for applying preclinical in-vivo pharmacology modalities in vitro, thereby bypassing the time required to create a specific knock-in/out strain for each genetic modification desired. Here, we describe a pipeline to directly genetically manipulate specific organoid systems in vitro. We first established organoid cultures from the small and large intestine of unique Tet-inducible RNAi mice where efficient gene knock-down can contribute to microsatellite instability. Using CRISPR/Cas9, we then edited these to generate CRC organoid models containing the BrafV600E mutation in combination with knock outs or knock-ins of cell cycle regulators and negative regulators of the Wnt pathway. These deficiencies mimic the progressive mutational changes upon acquisition BrafV600E. Our data lay the groundwork for future use of RNAi technology in combination with sequential gene editing for in vitro pharmacology and modeling diseases with complex genetic architecture both in vitro and in vivo. Citation Format: Prem K. Premsrirut, Huaien Wang, Eduardo J. Garcia Reino, Isabella Breen, Ana A. Vasileva. Utility of intestinal organoids to model serrated colon cancer in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 946.
Abstract 5307: Critical platforms of PROTAC validation
Authors: Ruifeng Wang
Journal: Cancer Research (2022)

Abstract In recent years, proteolysis targeting chimeric (PROTAC) technology has become an effective endogenous protein degradation tool in drug discovery. As a class of heterobifunctional small molecules, PROTACs recruit an E3 ubiquitin ligase to a given substrate protein, resulting in its targeted degradation through the endogenous ubiquitin-proteasome system (UPS). PROTAC consists of three chemical elements: a ligand that binds to a target protein, a ligand that binds to an E3 ubiquitin ligase, and a linker that connects the two ligands. Compared with traditional drug development, PROTAC technology possesses unique advantages including overcoming drug resistance and targeting the “undruggable”. Here we generated a kind of PROTAC target, like KRAS, BRD4, ESR1, associated cell lines to accelerate the discovery of new protein degradation drugs and the target protein degradation therapeutics by an optimized insertion system. In the beginning, we develop a system of different tag targeted cell lines, which can be easy to introduce HiBiT, Flag, GFP and also Halo Tag, et.al to target protein by CRISPaint or CRISPR Cas9 mediated HDR system. We also developed an arbitrary point mutation system based on the optimized PE3 mutation system, which can randomly modify any point mutation to simulate in vivo disease models in vitro. During this process, we have also optimized a series of validation system, like Targeted Protein Degradation (TPD), High-throughput flow cytometry (HTFC) and In-Cell Western (ICW) to shorten the detection time and improve detection stability. It is worth mentioning that we also develop a HiBiT and GFP dual-signal system, which can easily validate the target protein degradation and cell viability. We hope that our detection system can speed up the development of new drugs and contribute to human anti-tumor.Keywords: PROTAC, UPS, drug development, therapeutics Citation Format: Ruifeng Wang. Critical platforms of PROTAC validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5307.
Errors in Author Affiliations and Figure 2
Journal: JAMA Oncology (2022)

Lars Björnebo, MD, MSc; Tobias Nordström, MD, PhD; Andrea Discacciati, PhD; Thorgerdur Palsdottir, PhD; Markus Aly, MD, PhD; Henrik Grönberg, MD, PhD; Martin Eklund, PhD; Anna Lantz, MD, PhD
Abstract 345: Development of a novel and direct peptide Helicon࣪ inhibitor of β-catenin-TCF interaction with <i>in vivo</i> validation of transcriptional modulation and anti-tumor activity
Authors: Yaguang Si, Brian White, Sarah Cappucci, Jessica Ramirez, Charles Ponthier, Erica Visness, Kevin Ling, Peicheng Du, Minjung Choi, Ty Thomson, Josue Alfaro-Lopez, Pieter Beerepoot, Sorabh Agarwal, Paula Ortet, Miroslaw Lech, Zhi Li, Voké Olokpa, Ivan Jewett, Daniel La, Lihua Yu, John McGee, Martin Tremblay, Jonathan Hurov, Greg Verdine
Journal: Cancer Research (2022)

Abstract Wnt pathway mutations can be found in nearly all colorectal cancers and a significant number of cancers of the liver, breast, prostate, endometrium and lung, among others. β-catenin is a key signaling hub in the Wnt pathway. Activated nuclear β-catenin forms a complex with TCF/LEF (T-cell factor/lymphoid enhancer binding factor) and drives the transcription of genes essential for cancer cell proliferation, survival, and metabolism. Blocking the β-catenin-TCF/LEF interaction offers an attractive therapeutic strategy to treat a large population of patients with WNT pathway mutations. However, β-catenin is considered as an “undruggable” target because it lacks tractable hydrophobic pockets for small-molecule binding. To address this challenge, we have successfully discovered and developed Helicon࣪ peptides targeting the β-catenin-TCF/LEF interaction. Using this novel modality, linear peptides are locked in a helical structure via a proprietary tethering technology to yield macrocyclic stapled peptides. Our helicons exhibit picomolar β-catenin binding affinity and nanomolar anti-proliferative cell-based activity. Cells treated with lead helicons followed by unbiased RNAseq GSEA indicate that the WNT/β-catenin pathways represent the top downregulated transcriptional signatures after treatment. Furthermore, PRISM cell line screening of more than 900 cell lines reveals that the most sensitive lines are enriched with APC and CTNNB1 mutations. Mechanistically, helicon treatment reduces nuclear β-catenin and alters the levels of cyclin D2/D3 and p27 in the sensitive lines. In vivo, our helicons display favorable pharmacokinetic properties, broad tissue distribution, and potent anti-tumor effects. Taken together, our data demonstrate β-catenin-targeting Helicon࣪ peptides have the potential to become the next-generation class of therapeutics to treat cancers with defined genetic mutations. Citation Format: Yaguang Si, Brian White, Sarah Cappucci, Jessica Ramirez, Charles Ponthier, Erica Visness, Kevin Ling, Peicheng Du, Minjung Choi, Ty Thomson, Josue Alfaro-Lopez, Pieter Beerepoot, Sorabh Agarwal, Paula Ortet, Miroslaw Lech, Zhi Li, Voké Olokpa, Ivan Jewett, Daniel La, Lihua Yu, John McGee, Martin Tremblay, Jonathan Hurov, Greg Verdine. Development of a novel and direct peptide Helicon࣪ inhibitor of β-catenin-TCF interaction with in vivo validation of transcriptional modulation and anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 345.
Conventional or Drug-Eluting Beads? Randomized Controlled Study of Chemoembolization for Hepatocellular Carcinoma: JIVROSG-1302
Authors: Masafumi Ikeda, Yasuaki Arai, Yoshitaka Inaba, Toshihiro Tanaka, Shunsuke Sugawara, Yoshihisa Kodama, Takeshi Aramaki, Hiroshi Anai, Shinichi Morita, Yoshinori Tsukahara, Hiroshi Seki, Mikio Sato, Kenya Kamimura, Kimei Azama, Masakatsu Tsurusaki, Eiji Sugihara, Masaya Miyazaki, Tatsushi Kobayashi, Miyuki Sone
Journal: Liver Cancer (2022)

With the advent of effective systemic therapy, transarterial chemoembolization (TACE) is established as a highly effective locoregional treatment modality for carefully selected patients with hepatocellular carcinoma (HCC). This randomized controlled trial was conducted to clarify whether selective TACE with drug-eluting beads (DEB-TACE) loaded with epirubicin or selective conventional TACE (cTACE) with epirubicin-ethiodized oil might be more effective for obtaining complete response(CR) in patients with HCC.Between March 2016 and May 2019, Child-Pugh class A or B patients with unresectable HCC who were scheduled to receive selective TACE were randomly assigned at a 1:1 ratio to the DEB-TACE arm or the cTACE arm. The primary endpoint was the CR rate at 3 months, as evaluated according to the modified Response Evaluation Criteria in Solid Tumors by an independent review committee, and the secondary endpoints were the CR rate at 1 month and incidences of adverse events.A total of 200 patients (DEB-TACE, 99 patients; cTACE, 101 patients) were enrolled in the study. The CR rates at 3 months and 1 month were significantly higher in the cTACE arm (75.2%, 84.2%) as compared with the DEB-TACE arm (27.6%, 35.7%). However, the frequencies of adverse events of any grade, including pyrexia (DEB-TACE vs. cTACE, 19.4% vs. 45.5%, p = 0.0001), fatigue (5.1% vs. 15.8%, p = 0.0194), malaise (11.1% vs. 25.7%, p = 0.0103), appetite loss (12.1% vs. 28.7%, p = 0.0048), abdominal pain (12.1% vs. 23.8%, p = 0.0423), increased serum bilirubin (22.2% vs. 48.5%, p = 0.0002), hypoalbuminemia (43.4% vs. 60.3%, p = 0.0154), increased serum aspartate aminotransferase (35.7% vs. 81.2%, p < 0.0001), and increased serum alanine aminotransferase (35.7% vs. 77.2%, p < 0.0001), were also significantly higher in the cTACE arm than in the DEB-TACE arm.Selective cTACE appeared to have higher CR rates for local tumor control as compared to selective DEB-TACE for HCC. However, the frequency of postembolization syndrome was also significantly higher in the cTACE group than in the DEB-TACE group. Thus, to achieve CR, cTACE may be selected over DEB-TACE in patients who can be expected to tolerate postembolization syndrome.
Abstract 6028: Patient derived organoids demonstrate hallmark characteristics of small cell lung cancer
Authors: Joshua D'Rozario, Julie George, Roman Thomas
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers with an overall 5-year survival rate of 5-10%. Although transgenic mouse models and patient derived xenograft models have been shown to capture the heterogeneity and complexity of SCLC, the costs involved and timeframe of generating these models can be extensive. Furthermore, these models lack the ability to study the patients’ immune components and tumor microenvironment. Alternatively, in other cancer types in vitro methods to generate organoids have been successful in the hope to develop personalized patient derived organoids for screening and further downstream analyses. Here, we have generated and characterized small cell lung cancer patient-derived tumor organoids and confirmed that the organoids possess similar molecular characteristics, genetic profiles and morphological architectures to the corresponding patient tumor tissue. Organoids were shown to express hallmark features for SCLC, which included expression of neuroendocrine markers CD56, CHGA, INSM1 and SYP shown by immunohistochemistry. We suggest utilizing these organoids as SCLC patient models would be ideal for investigating the tumor microenvironment in SCLC, mechanisms between tumor immune cell interactions as well as assessing patients’ responses to therapy. Citation Format: Joshua D'Rozario, Julie George, Roman Thomas. Patient derived organoids demonstrate hallmark characteristics of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6028.
Diagnostic Accuracy of the 2016 Guideline-Based Echocardiographic Algorithm to Estimate Invasively-Measured Left Atrial Pressure by Direct Atrial Cannulation
Authors: Misun Pak, Takeshi Kitai, Atsushi Kobori, Yasuhiro Sasaki, Taiji Okada, Ryosuke Murai, Toshiaki Toyota, Kitae Kim, Natsuhiko Ehara, Makoto Kinoshita, Yutaka Furukawa
Journal: JACC. Cardiovascular imaging (2022)